We are using mice with genetic defects in craniofacial development or differences in susceptibility to teratogens as models to study the mechanisms involved in craniofacial malformation. Mutations that cause cleft lip, cleft palate, malocclusion and exencephaly have been found to have chondrocytes that produce altered cartilage matrix. Several different genetic defects in matrix biochemistry result in similar malformation syndromes. Another gene causes reduced keratinization of the oral and external epithelium with resultant malformations of the face and limbs revealing the important role of keratinization in maintaining developmental organization. Other genes that modify the action of teratogenic drugs are used to explore the mechanisms of teratogenesis and to develop sensitive test systems for recognition of teratogens. These mouse genetic test systems are produced using uniform, highly inbred, genetically defined strains and time mating resulting in control of stages of development for tests of target tissues at critical periods of susceptibility in vivo or in vitro. Cell from embryos of appropriate genetic type and developmental stage are labeled in vivo or in vitro with isotopic precursors for specific structural molecules in order to determine the mechanisms of gene action in development and the mechanisms of teratogenesis. These methods have proven successful in identification molecular defects in cartilage matrix and other specific molecular errors that result in malformation. We are continuing to use this approach to determine the molecular vocabulary of development.